Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1/NF-κB pathway

  • Author Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Jingling Zhao
    Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Shuai Yang
    Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Affiliations
    Department of Neurosurgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Bin Shu
    Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Lei Chen
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Ronghua Yang
    Affiliations
    Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan, China
    Search for articles by this author
  • Yingbin Xu
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Julin Xie
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Xusheng Liu
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Shaohai Qi
    Correspondence
    Correspondence to: Shaohai Qi* Address: NO. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, P. R. China
    Affiliations
    Department of Burns, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    # Jingling Zhao, Shuai Yang and Bin Shu make an equal contribution to this work
Published:November 28, 2020DOI:https://doi.org/10.1016/j.jid.2020.10.023

      Abstract

      The progression of diabetic complications does not halt despite termination of hyperglycemia, suggesting a “metabolic memory” phenomenon. However, whether metabolic memory exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that wound healing was delayed and angiogenesis was decreased in diabetic mice, despite normalization of glycemic control. Thus, we hypothesized that transient hyperglycemic spikes may be a risk factor for diabetic wound healing. We showed that transient hyperglycemia caused persistent damage to the vascular endothelium. Transient hyperglycemia directly upregulated DNMT1 expression, leading to the hypermethylation of Ang-1 and reduced Ang-1 expression, which, in turn, induced long-lasting activation of nuclear factor (NF)-κB and subsequent endothelial dysfunction. An in vivo study further showed that inhibition of DNMT1 promoted angiogenesis and accelerated diabetic wound healing by regulating the Ang-1/NF-κB signaling pathway. These results highlight the dramatic and long-lasting effects of transient hyperglycemic spikes on wound healing and suggest that DNMT1 is a novel target for diabetic vascular complications.

      Key words

      To read this article in full you will need to make a payment

      REFERENCES AND NOTES

        • Brownlee M.
        The pathobiology of diabetic complications: a unifying mechanism.
        Diabetes. 2005; 54: 1615-1625
        • Cho C.H.
        • Kim K.E.
        • Byun J.
        • Jang H.S.
        • Kim D.K.
        • Baluk P.
        • et al.
        Long-term and sustained COMP-Ang1 induces long-lasting vascular enlargement and enhanced blood flow.
        Circulation research. 2005; 97: 86-94
        • Costantino S.
        • Ambrosini S.
        • Paneni F.
        The epigenetic landscape in the cardiovascular complications of diabetes.
        J Endocrinol Invest. 2018;
        • Detich N.
        • Hamm S.
        • Just G.
        • Knox J.D.
        • Szyf M.
        The methyl donor S-Adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-Adenosylmethionine.
        The Journal of biological chemistry. 2003; 278: 20812-20820
        • Diabetes C.
        • Complications Trial Research G.
        • Nathan D.M.
        • Genuth S.
        • Lachin J.
        • Cleary P.
        • et al.
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • Dinh T.
        • Tecilazich F.
        • Kafanas A.
        • Doupis J.
        • Gnardellis C.
        • Leal E.
        • et al.
        Mechanisms involved in the development and healing of diabetic foot ulceration.
        Diabetes. 2012; 61: 2937-2947
        • Dinh T.L.
        • Veves A.
        The efficacy of Apligraf in the treatment of diabetic foot ulcers.
        Plast Reconstr Surg. 2006; 117 (7S; discussion 8S-9S): 152S
        • Dumville J.C.
        • Soares M.O.
        • O'Meara S.
        • Cullum N.
        Systematic review and mixed treatment comparison: dressings to heal diabetic foot ulcers.
        Diabetologia. 2012; 55: 1902-1910
        • Dunn L.
        • Prosser H.C.
        • Tan J.T.
        • Vanags L.Z.
        • Ng M.K.
        • Bursill C.A.
        Murine model of wound healing.
        J Vis Exp. 2013; e50265
        • Duraisamy A.J.
        • Mishra M.
        • Kowluru A.
        • Kowluru R.A.
        Epigenetics and Regulation of Oxidative Stress in Diabetic Retinopathy.
        Invest Ophthalmol Vis Sci. 2018; 59: 4831-4840
        • Edmonds M.
        Body of knowledge around the diabetic foot and limb salvage.
        J Cardiovasc Surg (Torino). 2012; 53: 605-616
        • Falanga V.
        • Eaglstein W.H.
        • Bucalo B.
        • Katz M.H.
        • Harris B.
        • Carson P.
        Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers.
        J Dermatol Surg Oncol. 1992; 18: 604-606
        • Fan F.
        • Stoeltzing O.
        • Liu W.
        • McCarty M.F.
        • Jung Y.D.
        • Reinmuth N.
        • et al.
        Interleukin-1beta regulates angiopoietin-1 expression in human endothelial cells.
        Cancer Res. 2004; 64: 3186-3190
        • Fetita L.S.
        • Sobngwi E.
        • Serradas P.
        • Calvo F.
        • Gautier J.F.
        Consequences of fetal exposure to maternal diabetes in offspring.
        J Clin Endocrinol Metab. 2006; 91: 3718-3724
        • Galiano R.D.
        • Michaels Jt
        • Dobryansky M.
        • Levine J.P.
        • Gurtner G.C.
        Quantitative and reproducible murine model of excisional wound healing.
        Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2004; 12: 485-492
        • Giacco F.
        • Brownlee M.
        Oxidative stress and diabetic complications.
        Circulation research. 2010; 107: 1058-1070
        • Goldin A.
        • Beckman J.A.
        • Schmidt A.M.
        • Creager M.A.
        Advanced glycation end products: sparking the development of diabetic vascular injury.
        Circulation. 2006; 114: 597-605
        • He D.K.
        • Shao Y.R.
        • Zhang L.
        • Shen J.
        • Zhong Z.Y.
        • Wang J.
        • et al.
        Adenovirus-delivered angiopoietin-1 suppresses NF-kappaB and p38 MAPK and attenuates inflammatory responses in phosgene-induced acute lung injury.
        Inhal Toxicol. 2014; 26: 185-192
        • Holman R.R.
        • Paul S.K.
        • Bethel M.A.
        • Matthews D.R.
        • Neil H.A.
        10-year follow-up of intensive glucose control in type 2 diabetes.
        N Engl J Med. 2008; 359: 1577-1589
        • Kaufman P.D.
        • Rando O.J.
        Chromatin as a potential carrier of heritable information.
        Curr Opin Cell Biol. 2010; 22: 284-290
        • Kowluru R.A.
        Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats.
        Diabetes. 2003; 52: 818-823
        • Kowluru R.A.
        • Shan Y.
        • Mishra M.
        Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy.
        Lab Invest. 2016; 96: 1040-1049
        • Lee C.
        • An D.
        • Park J.
        Hyperglycemic memory in metabolism and cancer.
        Horm Mol Biol Clin Investig. 2016; 26: 77-85
        • Lee S.W.
        • Kim W.J.
        • Choi Y.K.
        • Song H.S.
        • Son M.J.
        • Gelman I.H.
        • et al.
        SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier.
        Nat Med. 2003; 9: 900-906
        • Li S.L.
        • Reddy M.A.
        • Cai Q.
        • Meng L.
        • Yuan H.
        • Lanting L.
        • et al.
        Enhanced proatherogenic responses in macrophages and vascular smooth muscle cells derived from diabetic db/db mice.
        Diabetes. 2006; 55: 2611-2619
        • Li Y.
        • Reddy M.A.
        • Miao F.
        • Shanmugam N.
        • Yee J.K.
        • Hawkins D.
        • et al.
        Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation.
        The Journal of biological chemistry. 2008; 283: 26771-26781
        • Lu J.
        • Song G.
        • Tang Q.
        • Zou C.
        • Han F.
        • Zhao Z.
        • et al.
        IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-kappaB signaling.
        The Journal of clinical investigation. 2015; 125: 1839-1856
        • Lu Z.
        • Liu N.
        • Wang F.
        Epigenetic Regulations in Diabetic Nephropathy.
        J Diabetes Res. 2017; 2017: 7805058
        • Maunakea A.K.
        • Chepelev I.
        • Zhao K.
        Epigenome mapping in normal and disease States.
        Circulation research. 2010; 107: 327-339
        • Miao F.
        • Smith D.D.
        • Zhang L.
        • Min A.
        • Feng W.
        • Natarajan R.
        Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes.
        Diabetes. 2008; 57: 3189-3198
        • Mustoe T.A.
        • O'Shaughnessy K.
        • Kloeters O.
        Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis.
        Plast Reconstr Surg. 2006; 117: 35S-41S
        • Okano M.
        • Bell D.W.
        • Haber D.A.
        • Li E.
        DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.
        Cell. 1999; 99: 247-257
        • Olsen A.S.
        • Sarras Jr., M.P.
        • Leontovich A.
        • Intine R.V.
        Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression.
        Diabetes. 2012; 61: 485-491
        • Pierce J.W.
        • Schoenleber R.
        • Jesmok G.
        • Best J.
        • Moore S.A.
        • Collins T.
        • et al.
        Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo.
        The Journal of biological chemistry. 1997; 272: 21096-21103
        • Pirola L.
        • Balcerczyk A.
        • Okabe J.
        • El-Osta A.
        Epigenetic phenomena linked to diabetic complications.
        Nat Rev Endocrinol. 2010; 6: 665-675
        • Reddy M.A.
        • Natarajan R.
        Epigenetic mechanisms in diabetic vascular complications.
        Cardiovasc Res. 2011; 90: 421-429
        • Reddy M.A.
        • Natarajan R.
        Role of epigenetic mechanisms in the vascular complications of diabetes.
        Subcell Biochem. 2013; 61: 435-454
        • Robert M.F.
        • Morin S.
        • Beaulieu N.
        • Gauthier F.
        • Chute I.C.
        • Barsalou A.
        • et al.
        DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells.
        Nat Genet. 2003; 33: 61-65
        • Robertson K.D.
        • Wolffe A.P.
        DNA methylation in health and disease.
        Nat Rev Genet. 2000; 1: 11-19
        • Rodriguez H.
        • El-Osta A.
        Epigenetic Contribution to the Development and Progression of Vascular Diabetic Complications.
        Antioxid Redox Signal. 2018; 29: 1074-1091
        • Roy S.
        • Sala R.
        • Cagliero E.
        • Lorenzi M.
        Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory.
        Proc Natl Acad Sci U S A. 1990; 87: 404-408
        • Ruttermann M.
        • Maier-Hasselmann A.
        • Nink-Grebe B.
        • Burckhardt M.
        Local treatment of chronic wounds: in patients with peripheral vascular disease, chronic venous insufficiency, and diabetes.
        Dtsch Arztebl Int. 2013; 110: 25-31
        • Tewari S.
        • Zhong Q.
        • Santos J.M.
        • Kowluru R.A.
        Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy.
        Invest Ophthalmol Vis Sci. 2012; 53: 4881-4888
        • Turner R.C.
        • Cull C.A.
        • Frighi V.
        • Holman R.R.
        • Grp U.P.D.S.
        Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus - Progressive requirement for multiple therapies (UKPDS 49).
        Jama-J Am Med Assoc. 1999; 281: 2005-2012
        • Yancopoulos G.D.
        • Davis S.
        • Gale N.W.
        • Rudge J.S.
        • Wiegand S.J.
        • Holash J.
        Vascular-specific growth factors and blood vessel formation.
        Nature. 2000; 407: 242-248
        • Zhang L.
        • Zhang Q.
        • Liu S.
        • Chen Y.
        • Li R.
        • Lin T.
        • et al.
        DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury.
        Kidney Int. 2017; 92: 140-153
        • Zhao J.
        • Chen L.
        • Shu B.
        • Tang J.
        • Zhang L.
        • Xie J.
        • et al.
        Angiopoietin-1 protects the endothelial cells against advanced glycation end product injury by strengthening cell junctions and inhibiting cell apoptosis.
        Journal of cellular physiology. 2015; 230: 1895-1905